This multidisciplinary SCOR examines causes, consequences, and treatments of human hypertension. In 4 previous SCOR we characterized the renin- angiotensin-aldosterone axis as a cybernetic system regulating blood pressure, sodium-volume, and potassium homeostasis and defined its involvement in malignant and renovascular hypertensions and in bilateral adrenal cortical hyperplasia. Using renin-sodium profiling, biochemical heterogeneity of essential hypertension was described, the participation of plasma renin in hypertension of medium and high renin phenotypes demonstrated and its feedback suppression shown in the low-renin, sodium- volume phenotype. These data led us to the concept of anti-renin system drugs as a diagnostic and treatment strategy. This SCOR builds on this knowledge and expertise. A central theme is the renal basis for human hypertension. We will investigate our concept of nephron heterogeneity, i.e., discordance between hypofiltering high renin and adaptive hyperfiltering low renin nephrons, as a basis for the abnormal renin/sodium (vasoconstriction-volume) relationships that sustain hypertension. In man and animals at the system, organ and cell levels, we will study heterogeneity of nephron function, of angiotensin II receptors, renal renin supressibility and renal reserve. The role of prorenin as the mediator of a paracrine intrarenal renin system will be examined. The regulation of renin gene expression and biosynthesis will be characterized. A focal point of the program is the development of comprehensive nomographic data dynamically relating prorenin, renin, angiotensin II, and aldosterone to ANF, the calcium hormones and other adrenal steroids as dietary sodium and potassium intakes are changed. These data will enable us to examine the meaning of the relationships between renin, ANF and the other hormones in hypertension and in toxemia of pregnancy. We will examine mechanisms of white coat hypertension and study it further as a risk factor for heart damage. We will extend our population studies that document plasma renin as a risk factor for heart attack, and our experiments describing the role of renin and K+ in stroke and kidney damage in animals. Cardiac performance and LVH as factors in pathogenesis and outcome will be further defined. Overall, this program will define abnormal mechanisms in hypertension and will develop mechanistic criteria other than blood pressure to understand the evolution of target organ damage, assess prognosis and guide treatments.